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Retinoschisin gene therapy in photoreceptors, Müller glia or all retinal cells in the Rs1h−/− mouse

Gene Therapy volume 21, pages 585–592 (2014)Cite this article

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Abstract

X-linked retinoschisis, a disease characterized by splitting of the retina, is caused by mutations in the retinoschisin gene, which encodes a putative secreted cell adhesion protein. Currently, there is no effective treatment for retinoschisis, though viral vector-mediated gene replacement therapies offer promise. We used intravitreal delivery of three different AAV vectors to target delivery of the RS1 gene to Müller glia, photoreceptors or multiple cell types throughout the retina. Müller glia radially span the entire retina, are accessible from the vitreous, and remain intact throughout progression of the disease. However, photoreceptors, not glia, normally secrete retinoschisin. We compared the efficacy of rescue mediated by retinoschisin secretion from these specific subtypes of retinal cells in the Rs1h−/− mouse model of retinoschisis. Our results indicate that all three vectors deliver the RS1 gene, and that several cell types can secrete retinoschisin, leading to transport of the protein across the retina. The greatest long-term rescue was observed when photoreceptors produce retinoschisin. Similar rescue was observed with photoreceptor-specific or generalized expression, although photoreceptor secretion may contribute to rescue in the latter case. These results collectively point to the importance of cell targeting and appropriate vector choice in the success of retinal gene therapies.

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Acknowledgements

We thank Robert Molday for providing the 3R10 anti-RS1 antibody. We thank Bernhardt Weber and Bill Hauswirth for supplying the mouse model of XLRS. We thank Günter Niemeyer, Greg Nielsen and Matt LaVail for valuable advice on ERG recordings. We also thank Tim Day for assisting with plasmid cloning, and Jonathan Jui for helping with immunohistochemistry. This work was supported by funding from the NIH and FFB.

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Author notes

  1. D Dalkara

    Present address: 5Current address: Institut de la Vision, UMRS 968 UPMC, INSERM, CNRS U7210, F-75012 Paris, France.,

Authors and Affiliations

  1. Department of Molecular and Cellular Biology, The Helen Wills Neuroscience Institute, The University of California, Berkeley, CA, USA

    L C Byrne, B E Öztürk, T Lee, C Fortuny, M Visel, D Dalkara & J G Flannery

  2. Department of Chemical and Biomolecular Engineering, The Helen Wills Neuroscience Institute, The University of California, Berkeley, CA, USA

    L C Byrne, D Dalkara & D V Schaffer

  3. Department of Bioengineering, The Helen Wills Neuroscience Institute, The University of California, Berkeley, CA, USA

    L C Byrne, D Dalkara & D V Schaffer

  4. Department of Vision Science, The University of California, Berkeley, CA, USA

    C Fortuny & J G Flannery

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  1. L C Byrne
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Corresponding author

Correspondence to J G Flannery.

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Competing interests

DD, JGF and DVS are patent holders on ShH10 for gene delivery to the retina. LCB, DD, MV, JGF and DVS are patent holders on 7m8 for delivery of gene products to retinal cells.

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Byrne, L., Öztürk, B., Lee, T. et al. Retinoschisin gene therapy in photoreceptors, Müller glia or all retinal cells in the Rs1h−/− mouse. Gene Ther 21, 585–592 (2014). https://doi.org/10.1038/gt.2014.31

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  • DOI: https://doi.org/10.1038/gt.2014.31

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